Experimental and molecular pathology最新文献

英文中文

Wharton's jelly-derived nanovesicles for targeting intervertebral disc degeneration 针对椎间盘退变的沃顿果冻衍生纳米囊泡

IF 3.7 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-12-01 DOI: 10.1016/j.yexmp.2025.105011

Letizia Penolazzi , Alice Zaramella , Anna Chierici , Paola Bisaccia , Maria Pina Notarangelo , Anna Maria Tolomeo , Elisabetta Lambertini , Anna Alessia Saponaro , Tommaso Colangelo , Michela Pozzobon , Roberta Piva

The present study was designed to characterize the matrix-bound nanovesicles (MBVs) in decellularized Wharton's jelly matrix (DWJ). We have previously used DWJ as a biomaterial demonstrating its efficacy in restoring the functional properties of human intervertebral disc (IVD) cells lost following degeneration (IDD), for which there is currently no cure.

MBVs were isolated by ultracentrifugation from DWJ, characterized by transmission electron microscopy, nanoparticle tracking assay, and surface marker expression. MBVs uptake into cells was assessed by CalceinAM labeling. Nitric oxide production was evaluated by Griess assay. The response of IVD cells was assessed by cell motility (wound scratch assay) and protein expression (immunocytochemistry). MBVs were subjected to human growth factors array to evaluate different growth factors and global miRNA profiling (obtained from miRNA libraries, sequencing-NextSeq system and the GeneGlobe Data Analysis).

MBVs were readily internalized by cells without affecting the viability. MBVs suppressed the acquisition of the M1 phenotype in LPS-stimulated macrophages, positively influence the cell migration of IVD cells and the expression of molecular markers associated with the restoration of the chondrocyte-like phenotype. A preliminary analysis of growth factor content and miRNA expression profiling suggest that MBVs carry a cargo functionally relevant for the IVD cell metabolism.

The discovery of MBVs in DWJ leads to considering them as an integral component of DWJ-based scaffolds designed to repair or regenerate a damaged tissue. The pro-discogenic properties of MBVs demonstrate that there are grounds for expanding the study of DWJ-derived MBVs for potential therapeutic applications in the treatment of IDD.

本研究旨在表征脱细胞沃顿氏果冻基质（DWJ）中基质结合的纳米囊泡（mbv）。我们之前使用DWJ作为生物材料，证明其在恢复人类椎间盘（IVD）细胞在退变（IDD）后丢失的功能特性方面的功效，目前尚无治愈方法。采用超离心方法从DWJ中分离出mbv，通过透射电镜、纳米颗粒跟踪实验和表面标记物表达进行表征。CalceinAM标记法评估mbv对细胞的摄取。用Griess法测定一氧化氮产量。通过细胞运动（创面划痕试验）和蛋白表达（免疫细胞化学）评估IVD细胞的反应。mbv接受人类生长因子阵列来评估不同的生长因子和全局miRNA分析（来自miRNA文库、测序- nextseq系统和GeneGlobe数据分析）。mbv很容易被细胞内化而不影响细胞活力。mbv抑制lps刺激的巨噬细胞M1表型的获得，积极影响IVD细胞的细胞迁移和与软骨细胞样表型恢复相关的分子标记的表达。对生长因子含量和miRNA表达谱的初步分析表明，mbv携带了与IVD细胞代谢功能相关的货物。在DWJ中发现mbv使人们认为它们是基于DWJ的支架的一个组成部分，用于修复或再生受损组织。mbv的前椎间盘发生特性表明，有理由扩大dwj衍生的mbv的研究，以用于治疗IDD的潜在治疗应用。

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引用次数: 0

Expression of concern: "1,25-Dihydroxyvitamin D3 enhances neural stem cell proliferation and oligodendrocyte differentiation" [Experimental and Molecular Pathology 98 (2015) 240-245]. 关注表达：“1,25-二羟基维生素D3增强神经干细胞增殖和少突胶质细胞分化”[实验与分子病理学98(2015)240-245]。

IF 3.7 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-12-01 Epub Date: 2025-07-17 DOI: 10.1016/j.yexmp.2025.104985

引用次数: 0

Corrigendum to “Characteristics of liver fibrosis associated with chronic Opisthorchis felineus infection in Syrian hamsters and humans” [Experimental and Molecular Pathology 110 (2019) 104274] “叙利亚仓鼠和人类慢性猫腹绦虫感染相关肝纤维化特征”[实验与分子病理学110(2019)104274]的勘误。

IF 3.7 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-12-01 DOI: 10.1016/j.yexmp.2025.104975

Anna V. Kovner , Maria Y. Pakharukova , Galina A. Maksimova , Viatcheslav A. Mordvinov

引用次数: 0

Retraction notice to “Interferon alpha-2b inhibits negative-strand RNA and protein expression from full-length HCV1a infectious clone” [Experimental and Molecular Pathology 76 (2004) 242–252]. “干扰素α -2b抑制全长HCV1a感染克隆负链RNA和蛋白质表达”的撤回通知[实验与分子病理学76(2004)242-252]。

IF 3.7 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-12-01 DOI: 10.1016/j.yexmp.2025.104999

Ramesh Prabhu , Virendra Joshi , Robert F. Garry , Frank Bastian , Salima Haque , Fredric Regenstein , Swan Thung , Srikanta Dash

引用次数: 0

Prevalence and clinical significance of CBP deficiency and disturbed CBP expression in human cancer 人类肿瘤组织中CBP缺乏及表达紊乱的患病率及临床意义

IF 3.7 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-12-01 DOI: 10.1016/j.yexmp.2025.105012

Victoria Chirico , Tabea Lenkeit , Seyma Büyücek , Katharina Möller , Florian Lutz , Florian Viehweger , Martina Kluth , Claudia Hube-Magg , Christian Bernreuther , Guido Sauter , Andreas H. Marx , Ronald Simon , Till Krech , Stefan Steurer , Christoph Fraune , Sarah Minner , Natalia Gorbokon , Maximilian Lennartz , Eike Burandt , Anne Menz , Nina Schraps

CBP (CREB-binding protein) is a ubiquitously expressed major histone modifier involved in the regulation of thousands of genes. In cancer, loss-of-function and overexpression can occur. To clarify the role of CBP expression, a tissue microarray containing 14,966 samples from 134 different tumor entities and 608 samples of 76 different normal tissues was analyzed by immunohistochemistry. In normal tissues, strong nuclear CBP staining was ubiquitously seen except of few cell types. Among 12,255 evaluable tumors, CBP staining was completely absent (CBP deficiency) in 226 (1.84 %) while 232 (1.89 %) showed only faint to moderate staining of a minority of cancer cells (substantial reduction, SR), 384 (3.13 %) weak, 3079 (25.12 %) moderate, and 8334 (68.00 %) strong CBP positivity. CBP deficiency or SR was common in endometrioid endometrial carcinoma (22.8 %), hepatocellular carcinoma (19.0 %), urothelial carcinoma (up to 17.4 %), serous endometrial carcinoma (12.5 %), and chromophobe renal cell carcinoma (RCC; 10.7 %). Less than 10 % CBP deficient or SR cases were seen in >50 additional tumor categories. Among tumors with CBP expression, reduced expression was linked to high pT (p < 0.0001), high UICC stage (p = 0.0005) and poor grade (p < 0.0001) in clear cell RCC, high UICC stage (p = 0.0409) and distant metastasis (p = 0.0022) in papillary RCC, advanced pT stage (p = 0.0003) in colorectal carcinoma and invasive disease (p < 0.0001) and L1 status (p = 0.0154) in urothelial carcinoma. High CBP expression was related to nodal metastasis in pancreatic adenocarcinoma (p = 0.0201). In conclusion, CBP deficiency is a rare event in many different tumor types. Reduced or absent CBP expression is linked to aggressive cancer phenotypes.

CBP （creb结合蛋白）是一种普遍表达的主要组蛋白修饰因子，参与数千种基因的调控。在癌症中，可能会发生功能丧失和过度表达。为了明确CBP表达的作用，我们用免疫组织化学方法分析了包含134种不同肿瘤实体的14966个样本和76种不同正常组织的608个样本的组织芯片。在正常组织中，除少数细胞类型外，普遍可见强核CBP染色。在12255例可评估的肿瘤中，226例（1.84%）CBP染色完全缺失（CBP缺乏），232例（1.89%）显示少数癌细胞仅呈微弱至中度染色（实质性减少，SR）， 384例（3.13%）弱，3079例（25.12%）中度，8334例（68.00%）强CBP阳性。CBP缺乏或SR在子宫内膜样子宫内膜癌（22.8%）、肝细胞癌（19.0%）、尿路上皮癌（高达17.4%）、浆液性子宫内膜癌（12.5%）和憎色性肾细胞癌（10.7%）中很常见。在另外50种肿瘤类别中，CBP缺陷或SR病例不到10%。在CBP表达的肿瘤中，表达减少与透明细胞RCC的高pT （p < 0.0001）、高UICC分期（p = 0.0005）和低分级（p < 0.0001）、乳头状RCC的高UICC分期（p = 0.0409）和远处转移（p = 0.0022）、结直肠癌和侵袭性疾病的晚期pT分期（p = 0.0003）和尿路上皮癌的L1状态（p = 0.0154）有关。CBP高表达与胰腺腺癌淋巴结转移相关（p = 0.0201）。总之，CBP缺乏在许多不同的肿瘤类型中是罕见的。CBP表达的减少或缺失与侵袭性癌症表型有关。

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引用次数: 0

Corrigendum to “Upregulation of CDK7 in gastric cancer cell promotes tumor cell proliferation and predicts poor prognosis” [Experimental and Molecular Pathology 100 (2016) 514–521] “胃癌细胞CDK7上调促进肿瘤细胞增殖并预测预后不良”[实验与分子病理学100(2016)514-521]更正。

IF 3.7 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-12-01 DOI: 10.1016/j.yexmp.2025.104974

Qiuhong Wang , Manhua Li , Xunlei Zhang , Hua Huang , Jianfei Huang , Jing Ke , Haifang Ding , Jinzhang Xiao , Xiaohang Shan , Qingqing Liu , Bojun Bao , Lei Yang

引用次数: 0

SUMOylation and NEDDylation in kidney diseases 肾脏疾病中的SUMOylation和neddyylation

IF 3.7 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-11-21 DOI: 10.1016/j.yexmp.2025.105010

Zi-Han Chen , Dan Li , Jian-Yu Zhang , Bo-Yu Wei , Hai-Ling Zhao , Ping Li , Dan-Qian Chen

Kidney disease poses a serious threat to human health and life, while the lack of specific therapeutic targets hinders the treatment of kidney disease. Emerging evidence shows that post-translational modifications (PTMs), particularly SUMOylation and NEDDylation, two ubiquitin-like modifications, are potential therapeutic targets for kidney disease. SUMOylation and NEDDylation participate in the treatment of kidney diseases by regulating different substrate proteins and signaling pathways. In renal ischemia-reperfusion injury, the promotion of LKB1 SUMOylation and the inhibition of NEDDylation modification facilitate renal fibrosis, and the increase of HIF-1α deSUMOylation contributes to attenuating apoptosis and oxidative stress in the kidneys. In diabetic kidney disease (DKD), the suppression of IKKγ SUMOylation attenuates NF-κB inflammatory signaling, while the inhibition of STAT1 SUMOylation and RBMX SUMOylation alleviates renal fibrosis. Additionally, inhibiting Notch1 signaling SUMOylation reduces podocyte apoptosis and glomerular endothelial cell injury, while the suppression of RhoA NEDDylation decreases inflammation and fibrosis in DKD. Accumulated studies display the therapeutic effect of the activators and inhibitors of SUMOylation and NEDDylation against kidney diseases, such as TAK-981 and MLN4924. Therefore, SUMOylation and NEDDylation function as promising therapeutic targets for kidney diseases, and their activators and inhibitors may serve as novel candidates.

肾脏疾病严重威胁着人类的健康和生命，而缺乏特异性的治疗靶点阻碍了肾脏疾病的治疗。新出现的证据表明，翻译后修饰（PTMs），特别是SUMOylation和neddyylation，两种泛素样修饰，是肾脏疾病的潜在治疗靶点。SUMOylation和neddyylation通过调节不同的底物蛋白和信号通路参与肾脏疾病的治疗。在肾缺血再灌注损伤中，LKB1的summoylation的促进和neddyylation修饰的抑制促进了肾纤维化，HIF-1α deSUMOylation的增加有助于减轻肾脏的凋亡和氧化应激。在糖尿病肾病（DKD）中，IKKγ summo酰化的抑制可减弱NF-κB炎症信号，而STAT1 summo酰化和RBMX summo酰化的抑制可减轻肾纤维化。此外，抑制Notch1信号summoylation可减少足细胞凋亡和肾小球内皮细胞损伤，而抑制RhoA NEDDylation可减少DKD中的炎症和纤维化。积累的研究显示SUMOylation和neddyylation的激活剂和抑制剂对肾脏疾病的治疗作用，如TAK-981和MLN4924。因此，SUMOylation和neddyylation是肾脏疾病的有希望的治疗靶点，它们的激活剂和抑制剂可能是新的候选物。

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引用次数: 0

Persistent renin-angiotensin system and inflammatory dysregulation following COVID-19 impairs ischemic stroke recovery COVID-19后持续肾素-血管紧张素系统和炎症失调损害缺血性卒中恢复

IF 3.7 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-11-20 DOI: 10.1016/j.yexmp.2025.105009

Amy May Lin Quek , Ooiean Teng , Ju-Hea Park , Bernadette Guek Cheng Er , Erle Chuen Hian Lim , Raymond Chee Seong Seet

Previous studies indicate that stroke recovery is worse in patients with prior COVID-19, suggesting persistent biological perturbations. We investigated lingering renin-angiotensin system (RAS) and inflammatory alterations after COVID-19 to uncover mechanisms driving impaired ischemic stroke recovery. We conducted a prospective observational cohort study comparing clinical and molecular profiles of ischemic stroke patients with and without recent COVID-19 infection to age-matched healthy controls. Plasma angiotensin-(1–7), angiotensin II, and soluble ACE2 were quantified, high-throughput proteomic profiling was performed using the Olink® Explore platform, and RNA sequencing was conducted to identify molecular mechanisms related to COVID-19-associated stroke and stroke outcomes (90-day modified Rankin Scale (mRS)). A total of 189 participants (38 COVID-19-associated stroke, 77 non-COVID-19 stroke, and 74 healthy controls) were enrolled. COVID-19-associated stroke patients exhibited significantly higher proportions of cryptogenic strokes (21.1 % vs 10.4 %), earlier hospital presentation (mean 185 vs 310 min), greater use of endovascular thrombectomy (97.4 % vs. 52.6 %), yet poorer functional outcomes (mRS ≥3) at 3 months (73 % vs. 47 %, all p < 0.05). Both stroke groups showed elevated angiotensin-(1–7) levels compared to controls, but angiotensin II levels were notably higher only in non-COVID-19 stroke patients. Proteomic analysis revealed sustained elevation of interferon-gamma (IFN-γ) signaling in COVID-19-associated stroke patients. Reduced AKT3 levels emerged as a significant predictor of poor outcomes, independent of renin-angiotensin biomarkers (adjusted OR 0.40; 95 % CI 0.16–0.94). Stroke patients with low AKT3 levels and poor outcomes exhibited significant upregulation of ribosomal proteins (RPS15, RPS4X, RPS7, RPS18, RPSA, RPS27A, RPS13, RPS23), reflecting heightened translational stress. Persistent RAS and inflammatory dysregulation following COVID-19 may contribute to worse stroke recovery. Future studies should validate and investigate the therapeutic implications of these findings.

先前的研究表明，先前感染COVID-19的患者中风恢复更差，这表明存在持续的生物学干扰。我们研究了COVID-19后持续存在的肾素-血管紧张素系统（RAS）和炎症改变，以揭示缺血性卒中恢复受损的机制。我们进行了一项前瞻性观察队列研究，比较了近期感染和未感染COVID-19的缺血性卒中患者与年龄匹配的健康对照者的临床和分子特征。定量血浆血管紧张素-(1-7)、血管紧张素II和可溶性ACE2，使用Olink®Explore平台进行高通量蛋白质组学分析，并进行RNA测序以确定与covid -19相关的卒中和卒中结局（90天改良Rankin量表（mRS））相关的分子机制。共纳入189名参与者（38名与covid -19相关的卒中，77名非covid -19卒中和74名健康对照）。与covid -19相关的卒中患者在3个月时表现出更高的隐源性卒中比例（21.1%对10.4%），更早的住院时间（平均185分钟对310分钟），更多的血管内取栓术（97.4%对52.6%），但更差的功能结局（mRS≥3）(73%对47%，均p

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引用次数: 0

Prospective evaluation of copy number alterations validates chromosome 1q gain as an independent marker of poor prognosis in localized Ewing sarcoma 拷贝数改变的前瞻性评估验证了染色体1q增益是局部尤文氏肉瘤预后不良的独立标志。

IF 3.7 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-11-17 DOI: 10.1016/j.yexmp.2025.105008

Juan Díaz-Martín , Andreas Ranft , Maite Blanquer-Maceiras , Rosa Noguera , Carmen Salguero-Aranda , Daniel Delgado-Bellido , Laura Romero-Pérez , Uta Dirksen , Enrique de Álava

Background

Ewing sarcoma is a rare and aggressive tumor affecting mainly adolescents and young adults. Accurate risk stratification is critical for treatment tailoring, yet traditional clinical parameters lack sufficient predictive accuracy. While retrospective studies have identified potential molecular biomarkers, prospective validation is required for clinical implementation.

Methods

The international PROVABES consortium (PROspective Validation of Biomarkers in Ewing Sarcoma) aims to evaluate molecular prognostic markers in European patients treated under international phase III trials. This study focuses on copy number alterations (CNAs), in 305 primary tumors. Tissue microarrays were analyzed by FISH for chromosome 1q gain (n = 297) and 16q loss (n = 266). Genome-wide CNAs were further assessed using SNP arrays in 139 samples. Associations with clinical outcomes were evaluated via Kaplan-Meier and multivariate Cox regression, with event-free survival (EFS) and overall survival (OS) as endpoints.

Results

Chromosome 1q gain was significantly associated with shorter OS in both localized cases and the overall cohort, and with inferior EFS specifically in localized patients. In contrast, 16q loss showed no significant prognostic impact. Multivariate analysis confirmed 1q gain as an independent predictor of poor EFS in localized disease. Notably, a higher fraction of genome altered was associated with inferior OS and EFS not only in localized patients but also in the entire cohort, and remained an independent predictor of outcome despite the smaller subset analyzed.

Conclusions

This prospective study validates chromosome 1q gain as an independent marker of poor prognosis in localized Ewing sarcoma. Furthermore, the extent of genomic alteration emerges as a promising predictor of both OS and EFS. Incorporating these biomarkers may improve individualized risk stratification and ultimately enhance patient outcomes.

背景：尤文氏肉瘤是一种罕见的侵袭性肿瘤，主要影响青少年和青壮年。准确的风险分层是治疗的关键，但传统的临床参数缺乏足够的预测准确性。虽然回顾性研究已经确定了潜在的分子生物标志物，但临床实施需要前瞻性验证。方法：国际PROVABES联盟（尤因肉瘤生物标志物的前瞻性验证）旨在评估在国际III期试验中治疗的欧洲患者的分子预后标志物。本研究的重点是305种原发肿瘤的拷贝数改变（CNAs）。用FISH分析组织微阵列中染色体1q增加（n = 297）和16q丢失（n = 266）。在139个样本中使用SNP阵列进一步评估全基因组CNAs。以无事件生存期（EFS）和总生存期（OS）为终点，通过Kaplan-Meier和多变量Cox回归评估与临床结果的相关性。结果：染色体1q增加与局部病例和整体队列中较短的OS显著相关，并与局部患者较低的EFS特异性相关。相比之下，16q的损失对预后没有显著影响。多变量分析证实1q增益是局部疾病EFS差的独立预测因子。值得注意的是，不仅在局部患者中，而且在整个队列中，较高比例的基因组改变与较差的OS和EFS相关，尽管分析的子集较小，但仍然是结果的独立预测因子。结论：本前瞻性研究证实染色体1q增加是局部尤文氏肉瘤预后不良的独立标志。此外，基因组改变的程度是预测OS和EFS的一个很有希望的指标。结合这些生物标志物可以改善个体化的风险分层，最终提高患者的预后。

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引用次数: 0

Histopathological analysis reveals mild to moderate changes in BALB/c mice after short-term administration of a microemulsion loaded with epoxy-α-lapachone 组织病理学分析显示，短期给药环氧-α-lapachone微乳后BALB/c小鼠出现轻度至中度变化。

IF 3.7 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-10-31 DOI: 10.1016/j.yexmp.2025.105006

Luiz Filipe Gonçalves-Oliveira , Juliana Figueiredo Peixoto , Bernardo Acácio Santini Pereira , Nathalia Silva Carlos Oliveira , Flávia de Oliveira Cardoso , Davyson de Lima Moreira , Franklin Silva-Souza , Carlos Roberto Alves

The development of innovative treatments for American Cutaneous Leishmaniasis is crucial due to severe side effects of current treatment and the emergence of non-responder parasites. To address such a challenge the incorporation of epoxy-α-lapachone (ELAP) into a microemulsion (ME), named ELAP-ME, represents a promising therapeutic approach. In previous studies, ELAP-ME demonstrated efficacy in controlling infection in the BALB/c-Leishmania (Leishmania) amazonensis model, advancing in the technology readiness level with a drug prototype. To further validate its potential as a drug prototype, the histopathological effects of ELAP-ME were investigated in healthy BALB/c mice as a preclinical approach stage. Mice were administered with a fixed dose of ELAP-ME microemulsion (∼7 μg/kg) and evaluated at different short-term after administration (4, 12, and 24 h). Histopathological analysis of the liver, kidney, lung, heart, and brain revealed only mild alterations. These findings confirm the low toxicity profile of ELAP-ME, highlighting its safety and supporting its continued advancement as a pharmacological alternative for the treatment of leishmaniasis.

由于目前治疗的严重副作用和无反应寄生虫的出现，开发美国皮肤利什曼病的创新治疗方法至关重要。为了解决这一挑战，将环氧-α-拉帕酮（ELAP）掺入微乳液（ME）中，称为ELAP-ME，是一种很有前景的治疗方法。在之前的研究中，ELAP-ME在BALB/c-亚马逊利什曼原虫模型中显示出控制感染的有效性，并在药物原型的技术就绪水平上取得了进展。为了进一步验证其作为药物原型的潜力，ELAP-ME在健康BALB/c小鼠中作为临床前研究阶段进行了组织病理学研究。给小鼠注射固定剂量的ELAP-ME微乳（~ 7 μg/kg），并在给药后的不同时间内（4、12和24 h）进行评价。肝、肾、肺、心和脑的组织病理学分析显示只有轻微的改变。这些发现证实了ELAP-ME的低毒性，强调了其安全性，并支持其作为治疗利什曼病的替代药物的持续发展。

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引用次数: 0

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